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Genesis of Cardiac Arrhythmias Mike Hansen Biology Department Eastern CT State University Role of sodium channel deglycosylation in the genesis of cardiac arrhythmias The Journal of Biological Chemistry Vol. 276, pp. 28,197-28,2003 C. A. Ufret-Vincenty, D. J. Baro, W. J. Lederer, H. A. Rockman, L. E. Quinones, and L. F. Santana University of Puerto Rico, University of Maryland School of Medicine, and Duke University Medical Center Cardiac arrhythmias • • • • • ? Leading cause of death in patients with HF Contractile dysfunction Possibly due to prolonged AP: Change in ion currents and Ca+ signaling Is it deglycosylation? Methods • Used a mouse as a model for HF • It lacked expression of MLP • Compared with normal heart Ventricular myocytes •ECG measurements •Single cell a.p. Ion channels •Ion channels in cell membrane •Receive signal to open •Influx of sodium ions Action potential Results •ECG: longer QT intervals in MLP than WT (control) •Shows MLP is abnormal •AP of MLP and WT •Reveals a.p. were longer in MLP Sodium channels • Current-voltage relationship for sodium channels • MLP • WT •Indicates lower Na channel density in MLP Voltage dependence for Na channel inactivation • Slowing of inactivation of channels in MLP • How are theses changes produced? • Changes sufficient enough to produce a.p. changes? Expression of Na channels •Western blot •Electrophoresis • alpha subunit of channel • reduction in band in MLP relative to WT • due to heavy glycosylation •MLP less glycosylated Lack of Deglycosylation? • • • • MLP and WT exposed to neuroaminadase Reduces extracellular glycosylation Results on WT were similar to that of HF Glycosylation alters channels in HF ? Conclusion • • • • Altered a.p. play a role in arrhythmias Likely due to glycosylation of Na channels Neuroamindase effects on WT Good for mice, what about humans? ?